Metastasis is a major cause of morbidity in breast cancer patients so a deeper understanding of the mechanisms underlying this process is of obvious importance. We have identified a set of proteins, called Id proteins, which facilitate the early stages of breast cancer cell growth in the lung metastatic site and whose overexpression in breast cancer is associated with the ability of these cells to remain in an undifferentiated, stem-like state. These proteins appear to antagonize the mesenchymal, migratory state that allow cells in the primary tumor to initially break off from the tumor bulk and travel through the blood stream. Indeed, we postulate here that the Id proteins allow for breast cancer cells in circulation to reacquire an epithelial-like fate whereby growth and colonization are facilitated. In this proposal we will explore the mechanism whereby the Id proteins induce this recolonization phenotype by identifying the proteins that are affected by Id directly and indirectly. This section will be a collaboration with Joan Massague and Filippo Giancotti. In addition , we will identify the key mechanisms whereby Id itself is upregulated during the metastatic process under the control of the TGF? growth factor. This section will be a collaboration with Joan Massague. Finally, having identified a small molecule the affects the ability of Id proteins to associate with their target proteins, we will attempt to further develop this novel class of compounds for anti-metastatic efficacy in pre-clinical models. This section will be a collaboration with Neal Rosen, Larry Norton and Joan Massague.